Chemical process

ABSTRACT

A process for the preparation of the compound (1) or an acid addition salt thereof which comprises reacting a compound of formula (II), wherein R is an optionally substituted benzyl group under concomitant reduction and hydrogenolysis conditions, followed, if required, by isolation of the compound as an acid addition salt thereof.

[0001] The present invention relates to an improved process forpreparing an intermediate for use in the synthesis of Cholecystokinin(CCK) agonists.

[0002] WO94/24149 describes a class of 1,5-benzodiazepine derivativeshaving an agonist action at the CCK-A receptor.

[0003] A particular interesting group of 1,5-benzodiazepine derivativesdescribed therein may be represented by the general formula (A)

[0004] The compounds of formula A are conveniently prepared from the3-amino derivative (I).

[0005] WO94/24149 teaches that such 3-amino-1,5-benzodiazepinederivatives may be prepared by reduction of the correspondingphenylhydrazone and the preparation of the compound of formula (I) bythe reduction of the corresponding phenylhydrazone (B), is specificallydescribed in intermediate 11 therein.

[0006] Reduction of the hydrazone (B) to give the amine (I) also resultsin the formation of aniline. This is a highly toxic product, thegeneration of which should be avoided if at all possible in a commercialprocess and thus there is a need to find an alternative synthesis to theprimary amine (I) which avoids the generation of aniline and providesthe required product in good yield.

[0007] We have now found that the required amine (I) can be prepared inhigh yield and without the consequential generation of toxic by productsby concomitant reduction and hydrogenolysis of the corresponding oxime(II), wherein R is an optionally substituted benzyl group.

[0008] Thus the present invention provides for a process for preparingthe amine (I) by concomitant reduction and hydrogenolysis of the oxime(II) followed, if desired, by isolation of the compound as an acidaddition salt thereof.

[0009] The concomitant reduction and hydrogenolysis is convenientlycarried out using a Palladium catalyst e.g. Palladium on charcoalcatalyst in the presence of hydrogen or ammonium formate in a solventsuch as an alkanol e.g. ethanol, isopropanol or an aqueous ethanol, e.g.aqueous ethanol, or tetrahydrofuran

[0010] For the reaction the group R is conveniently benzyl or asubstituted benzyl group e.g. p-methoxybenzyl or benzhydryl. PreferablyR is benzyl

[0011] The oxime (II) may conveniently be prepared by reaction of theortho-phenylene diamine derivative (III)

[0012] with an activated derivative of the di-acid (IV), wherein R is anoptionally substituted benzyl group.

[0013] Conveniently, the activated derivative of the di acid (IV) is thecorresponding diacylhalide e.g. chloride and this is prepared in situ byreaction of the di-acid (IV) with an oxalyl halide e.g. oxalyl chloride.The reaction is conveniently carried out in an aprotic solvent such asan ester e.g. ethyl acetate, dichloromethane, toluene, or dimethoxyetheror mixtures thereof, and in the presence of dimethylformamide.

[0014] The di acid (IV) is conveniently prepared by reaction of adialkyl ketomalonate e.g. diethyl ketomalonate with the correspondinghydroxylamine derivative RONH₂ in a solvent such as an alkanol orindustrial methylated spirits and in the presence of a base e.g.pyridine, or sodium hydroxide followed, if required, by reaction withaqueous sodium hydroxide.

[0015] The following examples, which are non-limiting, illustrate theinvention.

[0016] In the Examples the abbreviations EtOAc=ethyl acetate;MeOH=methanol, DMF=N,N-dimethylformamide; IPA=isopropyl alcohol;IMS=industrial methylated spirits.

[0017] Intermediate 1

[0018] Diethyl 2-[(benzyloxy)imino]malonate

[0019] Di-ethylketomalonate (60 g) was added at 20° C. to a stirredsuspension of O-benzylhydroxylamine (57.8 g) in IMS (500 ml) containingpyridine (30 ml). The reaction was heated at 75° C. for 4 hr. Thereaction was cooled and solvents removed under reduced pressure. Theresidue was partitioned between EtOAc (500 ml) and water (300 ml) andthe organic layer separated, washed with water (250 ml) and dried overMgSO₄. Solvents were evaporated to give the title compound 95.3 g, as acolourless oil (99% th, ca 3% w/w residual EtOAc) which was used withoutfurther purification.

[0020] 1H NMR (300 MHz, CDCl₃) 7.4 (m, 5H), 5.35 (s, 2H), 4.35 (m, 4H),1.3 (m, 6H).

[0021] Intermediate 2

[0022] Method A

[0023] 2-[(benzyloxy)imino]malonic acid

[0024] To a solution of Intermediate 1 (40 g) in MeOH (80 ml) was added2M NaOH (200 ml) over 20 mins. The reaction was stirred at roomtemperature for 2 hr. MeOH was removed under reduced pressure and theresidual solution was acidified to pH 2 by dropwise addition of conc.HCl(˜30 ml) while cooling to maintain the temperature below 35° C. A thickwhite slurry was formed which was diluted with water (50 ml) to aidmobility. The solids were collected by filtration, washed with chilledwater (25 ml) and dried in vacuo at 55° C. to give the title compound asa white solid (17 g) found to contain ca.10% w/w residual inorganicsalts. Corrected yield ˜45% th. Used without further purification.

[0025] 1H NMR (300 MHz, D₂O) 7.4 (m, 5H), 5.2 (s, 2H)

[0026] Method B

[0027] 2-[(Benzyloxy)imino]malonic acid

[0028] To a solution of sodium hydroxide (5.74 g) in water (50 ml) andIMS (80 ml) was added benzylhydroxylamine hydrochloride (22.9 g).Diethyl ketomalonate (25 g,) was added and the mixture warmed to 60° C.and stirred for 4 h. The mixture was cooled to 30° C. and then addedover ˜10 minutes to a solution of sodium hydroxide (16.1 g) in water(180 ml) maintaining the internal temperature between 25-30° C. Themixture was stirred at 25° C. for ˜1 h. This solution was added to amixture of conc. hydrochloric acid (50 ml) in ethyl acetate (160 ml) andwater (20 ml) at 10° C. The rate of addition is controlled to maintainthe internal temperature below 15° C. The mixture was allowed to warm to25° C., and the phases were separated. The aqueous phase was extractedwith ethyl acetate (200 ml) and this wash was combined with the organicphase. The solution was concentrated to ˜100 ml by distillation underreduced pressure. Toluene (50 ml) was added and the mixture concentratedunder reduced pressure to ˜100 ml. Further toluene (150 ml) was addedand the mixture concentrated under reduced pressure to ˜100 ml andprecipitation of a white solid was observed. The solid was collected byfiltration and washed with toluene. The solid was dried in vacuo at 40°C. to give the title compound (24.4 g).

[0029] Intermediate 3

[0030]2-[-3-[(Benzyloxy)imino]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinyl)-N-isopropyl-N-phenylacetamide

[0031] Method A

[0032] Oxalyl chloride (38.3 g) was added dropwise (˜1 hr) to a stirredsuspension of Intermediate 2 (40 g, corrected for salt content to 31.4g) in EtOAc (200 ml) containing DMF (0.5 ml, 5 mol %). The mixture wasstirred at 25° C. for 0.5 hour then filtered through a pad of Dicalite,washing with EtOAc (40 ml) to give a clear yellow solution. The solutionwas added (˜5 mins) to a stirred slurry ofN-isopropyl-N-phenyl-2-(2-phenylaminophenylamino)-acetamide (50 g) inEtOAc (120 ml) at 25° C. The mixture was warmed to 60° C. and a darkpurple solution formed. After 1 hr, EtOAc (200 ml) was removed byatmospheric distillation. IPA (120 ml) and water (40 ml) were added andthe mixture distilled further to remove more solvent (80 ml). IPA (40ml) and water (40 ml) were added and a further amount of solvent wasdistilled out (80 ml). The reaction mixture was cooled to 25° C. over1.5 hr and the solids collected by filtration. The solids were washedwith IPA (2×120 ml), water (1×120 ml) and finally IPA again (1×40 ml)then dried in vacuo at 55° C. to give the title compound as a powder(56.6 g).

[0033] 1H NMR (300 MHz, CDCl₃) 2:1 mixture of isomers about the oxime7.6-6.95 (m. 18H), 6.9 (t 1H), 5.3 (m, 2H), 4.95 (m, H), 4.65 (d,0.33H), 4.4 (d, 0.67H), 4.1 (d, 0.67H), 4.0 (d, 0.33H), 0.95 (m, 6H)

[0034] Method B

[0035] Oxalyl chloride (143 g) was added dropwise over ˜1 h to a stirredsolution of 2-[(benzyloxy)imino]malonic acid (123 g) in ethyl acetate(250 ml) containing N,N-dimethylformamide (1.2 g) at 25° C. Thehomogeneous mixture was stirred for 2 hr. The solution was added over ˜1h to a stirred slurry ofN-isopropyl-N-phenyl-2-(2-phenylamino)-acetamide (198 g) in ethylacetate (800 ml) at 60° C. The reaction mixture was stirred at 60° C.for at least 1.5 h. The mixture (suspension) was cooled to 30° C. andisopropanol (200 ml) was added and the suspension stirred overnight. Thesolid was collected by filtration, washing with isopropanol and dried at55° C. in vacuo to yield the title compound as a pale yellow solid (187g).

EXAMPLE 1(±)-2-(3-Amino-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo-[b][1,4]diazepen-1-yl)-N-isopropyl-N-phenylacetamide

[0036] Method A

[0037] To a stirred suspension of Intermediate 3 (3 g) and ammoniumformate (2.08 g) in IMS (30 ml) and water (3 ml) was added 5% Pd/C (50%w/w water) (0.25 g). The mixture was heated under a nitrogen atmosphereat 60° C. overnight. The hot reaction mixture was filtered throughDicalite to remove the catalyst. The catalyst was washed with hot IMS(60 ml) and filtered. The filtrates were concentrated under reducedpressure to give the title compound as a white solid (2.34 g).

[0038] Method B

[0039]2-[3-[(Benzyloxy)imino]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinyl)-N-isopropyl-N-phenylacetamide(10 g) was suspended in IMS (100 ml) with 5% Pd/C (50% wet) (1.5 g, 15%w/w) and heated at 70° C. for ˜6 hr under a hydrogen atmosphere at 5 barpressure. The mixture was cooled and THF (50 ml) was added. The mixturewas heated to reflux for 2 hours and filtered hot under nitrogen toremove the catalyst. The mixture was concentrated by distillation to ˜50ml with precipitation of the product. The solid is isolated byfiltration and washed with IMS (10 ml) and dried in vacuo at 55° C. toyield the title compound as a white solid (7.0 g).

[0040]¹H NMR (500 MHz, d₅-DMSO+D₂O) δ0.9 (m, 6H), 4.15 (d, J=12 Hz, 1H),4.4 (m, 1H), 4.7 (m, 1H), 4.9 (s, 1H), 6.9 (d, J=5 Hz, 1H), 7.2-7.6 (m,13H).

1. A process for the preparation of the compound of formula (I)

or an acid addition salt thereof which comprises reacting a compound of formula (II)

wherein R is an optionally substituted benzyl group under concomitant reduction and hydrogenolysis conditions, followed, if required, by isolation of the compound as an acid addition salt thereof.
 2. A process as claimed in claim 1 wherein the concomitant reduction and hydrogenolysis is carried out using a palladium catalyst.
 3. A process as claimed in claim 1 or claim 2 wherein the concomitant reduction and hydrogenolysis is carried out using hydrogen or ammonium formate
 4. A process as claimed in any of claims 1 or claim 3 wherein the compound of formula (II) has been prepared by reaction of the ortho phenylene diamine derivative (III) with an activated derivative of the di-acid (IV),

wherein R is an optionally substituted benzyl group.
 5. A process as claimed in claim 4 wherein the activated derivative of the di-acid (IV) is the di-acylchloride.
 6. A process as claimed in any of claims 1 to 5 wherein R is benzyl. 